Abstract
CAR T cells engineered to express heparanase exhibit increased ECM invasion and antitumor activity.
Major finding: CAR T cells engineered to express heparanase exhibit increased ECM invasion and antitumor activity.
Concept: Heparanase is required for T-cell extravasation and is downregulated in ex vivo–expanded T cells.
Impact: Heparanase expression may enhance the efficacy of CAR T cells in stroma-rich solid tumors.
Although adoptive transfer of ex vivo–expanded tumor-specific chimeric antigen receptor (CAR)–modified T cells has shown clinical activity in hematologic cancers, this approach has been less effective in stroma-rich solid tumors. Caruana and colleagues hypothesized that ex vivo manipulation may reduce CAR T-cell extravasation and accumulation in tumor sites by impairing the ability of these cells to degrade the extracellular matrix (ECM). Consistent with this idea, compared with briefly activated T cells, long-term ex vivo–expanded (LTE) human T cells exhibited diminished ECM invasion and lacked expression of heparanase, an enzyme that is upregulated in activated immune cells and required for cleavage of heparin sulfate proteoglycans in the ECM. Downregulation of the heparanase gene HPSE was observed across various T-cell subsets and correlated with accumulation of full-length p53 and increased p53 binding to the HPSE promoter in LTE T cells, suggesting that p53 may mediate HPSE repression. Intriguingly, tumor antigen–specific CAR–expressing LTE T cells engineered to stably express HPSE showed improved capacity to degrade ECM and enhanced ex vivo antitumor activity in the presence of ECM compared with control LTE T cells. Furthermore, infusion of HPSE-expressing CAR-positive LTE T cells resulted in increased T-cell infiltration, greater reduction of tumor growth, and improved survival in neuroblastoma and melanoma xenograft models. Importantly, induction of HPSE expression did not affect the viability, expansion, or cytolytic effector activity of CAR-expressing LTE T cells, and did not induce nonspecific accumulation of LTE T cells in normal lung or liver tissue. These findings suggest that restoration of HPSE expression in LTE T cells may augment the efficacy of tumor-specific CAR-modified T cells in patients with stroma-rich solid tumors.
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